Substituted heteroaromatic compounds: effect on nicotine self-administration in rats

Rationale

Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported.

Objectives

We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats.

Methods

Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03?mg/kg/infusion in 0.1?ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5–25?mg/kg, i.p., 30?min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11.

Results

Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED₅₀ values 4 and 2.8?mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds.

Conclusion

The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.